Inhibitors of farnesyl-protein transferase

ABSTRACT

The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.

This application is a based on Provisional Application No. 60/014,668filed Apr. 3, 1996.

BACKGROUND OF THE INVENTION

The present invention relates to compounds which inhibit farnesylprotein transferase, a protein which is implicated in the oncogenicpathway mediated by Ras. The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Rasand N-Ras) are part of a signalling pathway that links cell surfacegrowth factor receptors to nuclear signals initiating cellularproliferation. Biological and biochemical studies of Ras action indicatethat Ras functions like a G-regulatory protein. In the inactive state,Ras is bound to GDP. Upon growth factor receptor activation Ras isinduced to exchange GDP for GTP and undergoes a conformational change.The GTP-bound form of Ras propagates the growth stimulatory signal untilthe signal is terminated by the intrinsic GTPase activity of Ras, whichreturns the protein to its inactive GDP bound form (D. R. Lowy and D. M.Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ras genes(Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers,including colorectal carcinoma, exocrine pancreatic carcinoma, andmyeloid leukemias. The protein products of these genes are defective intheir GTPase activity and constitutively transmit a growth stimulatorysignal.

Ras must be localized to the plasma membrane for both normal andoncogenic functions. At least 3 post-translational modifications areinvolved with Ras membrane localization, and all 3 modifications occurat the C-terminus of Ras. The Ras C-terminus contains a sequence motiftermed a "CAAX" or "Cys-Aaa¹ -Aaa² -Xaa" box (Cys is cysteine, Aaa is analiphatic amino acid, the Xaa is any amino acid) (Willumsen et al.,Nature 310:583-586 (1984)). Depending on the specific sequence, thismotif serves as a signal sequence for the enzymes farnesyl-proteintransferase or geranylgeranyl-protein transferase, which catalyze thealkylation of the cysteine residue of the CAAX motif with a C₁₅ or C₂₀isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386(1992); W. R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237(1992)). Ras proteins are known to undergo post-translationalfarnesylation. Other farnesylated proteins include the Ras-relatedGTP-binding proteins such as Rho, fungal mating factors, the nuclearlamins, and the gamma subunit of transducin. James, et al., J. Biol.Chem. 269, 14182 (1994) have identified a peroxisome associated proteinPxf which is also farnesylated. James, et al., have also suggested thatthere are farnesylated proteins of unknown structure and function inaddition to those listed above.

Inhibition of farnesyl-protein transferase has been shown to block thegrowth of Ras-transformed cells in soft agar and to modify other aspectsof their transformed phenotype. It has also been demonstrated thatcertain inhibitors of farnesyl-protein transferase selectively block theprocessing of the Ras oncoprotein intracellularly (N. E. Kohl et al.,Science, 260:1934-1937 (1993) and G. L. James et al., Science,260:1937-1942 (1993). Recently, it has been shown that an inhibitor offarnesyl-protein transferase blocks the growth of ras-dependent tumorsin nude mice (N. E. Kohl et al., Proc. Natl. Acad. Sci U.S.A.,91:9141-9145 (1994) and induces regression of mammary and salivarycarcinomas in ras transgenic mice (N. E. Kohl et al., Nature Medicine,1:792-797 (1995).

Indirect inhibition of farnesyl-protein transferase in vivo has beendemonstrated with lovastatin (Merck & Co., Rahway, N.J.) and compactin(Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science245:379 (1989)). These drugs inhibit HMG-CoA reductase, the ratelimiting enzyme for the production of polyisoprenoids including farnesylpyrophosphate. Farnesyl-protein transferase utilizes farnesylpyrophosphate to covalently modify the Cys thiol group of the Ras CAAXbox with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaberet al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science,249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA,87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesisby inhibiting HMG-CoA reductase blocks Ras membrane localization incultured cells. However, direct inhibition of farnesyl-proteintransferase would be more specific, and thus preferable.

Inhibitors of farnesyl-protein transferase (FPTase) have been describedin two general classes. The first are analogs of farnesyl diphosphate(FPP), while the second class of inhibitors is related to the proteinsubstrates (e.g., Ras) for the enzyme. The peptide derived inhibitorsthat have been described are generally cysteine containing moleculesthat are related to the CAAX motif that is the signal for proteinprenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al.,PNAS, 88:732-736 (1991)). Such inhibitors may inhibit proteinprenylation while serving as alternate substrates for thefarnesyl-protein transferase enzyme, or may be purely competitiveinhibitors (U.S. Pat. No. 5,141,851, University of Texas; N. E. Kohl etal., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37,725 (1994)).

It has recently been reported that FPT-ase inhibitors also inhibit theproliferation of vascular smooth muscle cells and are therefore usefulin the prevention and treatment of arteriosclerosis and diabeticdisturbance of blood vessels (JP H7-112930).

It has recently been disclosed that certain tricyclic compounds whichoptionally incorporate a piperidine moiety are inhibitors of FPTase (WO95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitorsof farnesyl protein transferase have also been disclosed (WO 95/09001and EP 0 675 112 A1).

SUMMARY OF THE INVENTION

The present invention addresses a compound of formula I: ##STR1## or apharmaceutically acceptable salt thereof, wherein:

R^(1a), R^(1b) and R² are independently selected from the groupconsisting of: hydrogen, aryl, heterocyclyl, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R⁸ O--, R⁹ S(O)_(m) --, (R⁸)₂ NC(O)--, R⁸C(O)NR⁸ --, CN, NO₂, (R⁸)₂ NC(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, N₃,--N(R⁸)₂, R⁹ OC(O)NR⁸ -- and C₁ -C₆ alkyl, unsubstituted or substitutedby 1-3 groups selected from the group consisting of: halo, aryl,heterocyclyl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R⁸O--, R⁹ S(O)_(m) --, R⁸ C(O)NR⁸ --, CN, (R⁸)₂ NC(NR⁸)--, R⁸ C(O)--, R⁸OC(O)--, N₃, --N(R⁸)₂ and R⁹ OC(O)NR⁸ --;

R³ and R⁴ are independently selected from the group consisting of: H, F,Cl, Br, --NR⁸ ₂, CF₃, NO₂, R⁸ O--, R⁹ S(O)_(m) --, (R⁸)₂ NC(O)--, R⁸C(O)NH--, H₂ NC(NH)--, R⁸ C(O)--, R⁸ OC(O)--, N₃, CN, R⁹ OC(O)NR⁸ --, C₁-C₂₀ alkyl, substituted or unsubstituted aryl and substituted orunsubstituted heterocyclyl;

A³ is selected from: --NR⁵ S(O)_(m) -- or --S(O)_(m) NR⁵ --, with mequal to 0, 1 or 2, and R⁵ selected from the group consisting of:hydrogen, unsubstituted or substituted aryl, unsubstituted orsubstituted heterocyclyl, unsubstituted or substituted C₃ -C₁₀cycloalkyl, and C₁ -C₆ alkyl, unsubstituted or substituted with 1-3members selected from the group consisting of: unsubstituted orsubstituted aryl, unsubstituted or substituted heterocyclyl,unsubstituted or substituted C₃ -C₁₀ cycloalkyl, --N(R⁸)₂, --CF₃, --NO₂,(R⁸)O--, (R⁹)S(O)_(m) --, (R⁸)C(O)NH--, H₂ NC(NH)--, (R⁸)C(O)--,(R⁸)OC(O)--, N₃, CN and (R⁹)OC(O)NR⁸ --;

R⁶ and R⁷ are independently selected from the group consisting of:hydrogen, aryl, heterocyclyl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, C₁₋₆ perfluoroalkyl, F, Cl, Br, R⁸ O--, R⁹ S(O)_(m) --, R⁸C(O)NR⁸ --, CN, NO₂, (R⁸)₂ NC(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, N₃,--N(R⁸)₂, R⁹ OC(O)NR⁸ -- and C₁ -C₆ alkyl unsubstituted or substitutedby 1-3 groups selected from: aryl, heterocyclyl, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R⁸ O--, R⁹S(O)_(m) --, R⁸ C(O)NR⁸ --, CN, (R⁸)₂ NC(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--,N₃, --N(R⁸)₂ and R⁹ OC(O)NR⁸ --;

each R8 is independently selected from hydrogen, C₁ -C₆ alkyl, aryl andaralkyl;

each R⁹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from the group consisting of: abond, --CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR⁸ --, --NR⁸ C(O)--,--O--, --N(R⁸)--, --S(O)₂ N(R⁸)--, --N(R⁸)S(O)₂ --, and S(O)_(m) ;

X represents aryl or heteroaryl;

V is selected from the group consisting of: hydrogen, heterocyclyl,aryl, C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and C₂ -C₂₀ alkenyl, provided thatV is not hydrogen if A¹ is S(O)_(m) and V is not hydrogen if A¹ is abond, n is 0 and A² is S(O)_(m) ;

W represents heterocyclyl;

each n and p independently represents 0, 1, 2, 3 or 4;

r is 0 to 5, provided that r is 0 when V is hydrogen, and

t is 0 or 1.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are useful in the inhibition offarnesyl-protein transferase and the farnesylation of the oncogeneprotein Ras, and thus are useful for the treatment of cancer.

The compounds of the present invention may have asymmetric centers andoccur as racemates, racemic mixtures and as individual diastereomers,with all possible isomers, including optical isomers, being included inthe present invention.

When any variable (e.g. aryl, heterocycle, R¹, R² etc.) occurs more thanone time in any constituent, each definition is independent.

The term "alkyl" and the alkyl portion of alkoxy, aralkyl and similarterms, is intended to include branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms, or 1-6 carbon atoms if unspecified. Cycloalkyl means 1-2cabocyclic rings which are saturated and contain from 3-10 atoms.

"Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.

As used herein, "aryl" and the aryl portion of aralkyl, are intended tomean any stable monocyclic or bicyclic carbon ring of up to 7 members ineach ring, wherein at least one ring is aromatic. Examples of such arylelements include phenyl, naphthyl, tetrahydronaphthyl, indanyl,biphenyl, phenanthryl, anthryl or acenaphthyl. A preferred aralkyl groupis benzyl.

The terms heterocyclyl, heterocycle and heterocyclic, as used herein,mean a 5- to 7-membered monocyclic or 8- to 11-membered bicyclicheterocyclic rings, either saturated or unsaturated, aromatic, partiallyaromatic or non-aromatic, and which consist of carbon atoms and from oneto four heteroatoms selected from the group consisting of N, O, and S.Thus, it includes any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The ring or ring systemmay be attached at any heteroatom or carbon atom which results in astable structure, and may contain 1-3 carbonyl groups. Examples of suchheterocycles include, but are not limited to, azepinyl, benzimidazolyl,benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl,benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl,imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl,isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl,2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl,pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl,pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl,thienothienyl, and thienyl.

"Heteroaryl" is a subset of heterocyclic, and means a monocyclic orbicyclic ring system, with up to 7 members in each ring, wherein atleast one ring is aromatic and wherein from one to four carbon atoms arereplaced by heteroatoms selected from the group consisting of N, O, andS. Examples include benzimidazolyl, benzisoxazolyl, benzofurazanyl,benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl,benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl,isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl,pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl and thienyl.

Lines drawn into ring systems from substituents indicate that the bondmay be attached to any of the substitutable ring atoms.

The term "substituted" as used with respect to, e.g., substituted alkyl,substituted aryl, substituted heterocyclyl and substituted cycloalkylmean alkyl, aryl, heterocyclyl and cycloalkyl groups, respectively,having from 1-3 substituents which are selected from: halo, aryl,heterocyclyl, C₃₋₁₀ cycloalkyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,R⁸ O--, R⁹ S(O)_(m) --, R⁸ C(O)NR⁸ --, CN, (R⁸)₂ NC(NR⁸)--, R⁸ C(O)--,R⁸ OC(O)--, N₃, --N(R₈)₂ and R⁹ OC(O)NR⁸ --.

Preferably 1-2 groups are present on substituted alkyl, substitutedaryl, substituted heterocyclyl and substituted cycloalkyl, which areselected from: halo, aryl, R⁸ O--, CN, R⁸ C(O)-- and --N(R⁸)₂.

Preferably, R^(1a), R^(1b) and R² are independently selected from:hydrogen, --N(R⁸)₂, R⁸ C(O)NR⁸ -- or unsubstituted or substituted C₁ -C₆alkyl wherein the substituent on the substituted C₁ -C₆ alkyl isselected from unsubstituted or substituted aryl, --N(R⁸)₂, R⁸ O-- and R⁸C(O)NR⁸ -- Preferably, R³ and R⁴ are selected from: hydrogen and C₁ -C₆alkyl.

Preferably, A³ represents NR⁵ S(O)_(m), wherein m represents 2 and R⁵represents hydrogen.

Preferably, R⁶ represents hydrogen, unsubstituted or substituted C₁ -C₆alkyl.

Preferably R⁷ represents H or unsubstituted C₁₋₆ alkyl.

Preferably, R⁸ represents H or C₁₋₆ alkyl, and R⁹ is C₁₋₆ alkyl.

Preferably, A¹ and A² are independently selected from: a bond, --C(O)NR⁸--, --NR⁸ C(O)--, --O--, --N(R⁸)--, --S(O)₂ N(R⁸)-- and --N(R⁸)S(O)₂ --.

Preferably X represents aryl and most preferably phenyl.

Preferably, V is selected from hydrogen, heterocyclyl and aryl. Morepreferably V is phenyl.

Preferably, W is heterocyclyl selected from imidazolinyl, imidazolyl,oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. Morepreferably, W is selected from imidazolyl and pyridyl.

Preferably, m is 2.

Preferably n and p are independently 0, 1, 2 or 3.

Preferably t is 1.

A subset of compounds of the invention is represented by formula Ia:##STR2## wherein:

R³, R⁴, A³, R⁸, R⁹, m, n, p and r are as originally defined;

each R^(1a) and R² is independently selected from hydrogen and C₁ -C₆alkyl;

each R^(1b) is independently selected from: hydrogen, aryl,heterocyclyl, C₃₋₁₀ cycloalkyl, C₂₋₆ alkenyl, R⁸ O--, --N(R⁸)₂ and C₁-C₆ alkyl unsubstituted or substituted by aryl, heterocyclyl,cycloalkyl, alkenyl, R⁸ O-- and --N(R⁸)₂ ;

R⁵ is selected from the group consisting of: hydrogen and C₁ -C₆ alkyl,unsubstituted or substituted with 1-3 members selected from the groupconsisting of: unsubstituted or substituted aryl, unsubstituted orsubstituted heterocyclyl, unsubstituted or substituted C₃ -C₁₀cycloalkyl, --N(R⁸)₂, --CF₃, --NO₂, (R⁸)O--, (R⁹)S(O)_(m) --,(R⁸)C(O)NH--, H₂ NC(NH)--, (R⁸)C(O)--, (R⁸)OC(O)--, N₃, CN and(R⁹)OC(O)NR⁸ --;

R⁶ is selected from: hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R⁸ O--, R⁸ C(O)NR⁸ --, CN, NO₂,(R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --,and C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R⁸ O--, R⁸C(O)NR⁸ --, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, --N(R⁸)₂ and R⁹OC(O)NR⁸ --;

R⁷ is hydrogen or unsubstituted C₁₋₆ alkyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR⁸ --, O, --N(R⁸)-- and S(O)_(m) ;

and V is selected from: hydrogen; aryl; heterocyclyl selected frompyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl and thienyl; C₁-C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and C₂ -C₂₀ alkenyl, provided thatV is not hydrogen if A¹ is S(O)_(m) and V is not hydrogen if A¹ is abond and A² is S(O)_(m).

A second subset of compounds of the present invention is represented byformula Ib: ##STR3## wherein:

R^(1a), R^(1b), R², A¹, A², R³, R⁴, R⁵, R⁶, R⁸, R⁹, m, n, p and r are asoriginally defined;

R⁷ is selected from: hydrogen and unsubstituted C₁ -C₆ alkyl;

V is selected from: hydrogen, heterocyclyl selected from pyrrolidinyl,imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl,quinolinyl, isoquinolinyl, and thienyl, aryl, C₁ -C₂₀ alkyl wherein from0 to 4 carbon atoms are replaced with a heteroatom selected from O, S,and N, and C₂ -C₂₀ alkenyl, provided that V is not hydrogen if A¹ isS(O)_(m) and V is not hydrogen if A¹ is a bond, n is 0 and A² isS(O)_(m) ; and

W represents heterocyclyl selected from pyrrolidinyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl andisoquinolinyl.

A third embodiment of the invention is described in accordance withformula Ic: ##STR4## wherein:

each R² is independently selected from hydrogen and C₁ -C₆ alkyl;

R³, R⁴, A³, R⁸, R⁹, m and p are as originally defined;

each R⁵ is selected from: hydrogen and C₁ -C₆ alkyl unsubstituted orsubstituted with 1-3 groups selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclyl, unsubstituted orsubstituted C₃ -C₁₀ cycloalkyl, --N(R⁸)₂, --CF₃, --NO₂, (R⁸)O--,(R⁹)S(O)_(m) --, (R⁸)C(O)NH--, H₂ NC(NH)--, (R⁸)C(O)--, (R⁸)OC(O)--, N₃,--CN and (R⁹)OC(O)NR⁸ --;

and R⁶ is selected from the group consisting of: hydrogen, C₁ -C₆ alkyl,C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R⁸ O--, R⁸C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, --N(R⁸)₂,or R⁹ OC(O)NR⁸ -- and C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl,R⁸ O--, R⁸ C(O)NR⁸ --, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O), R⁸ OC(O)--, --N(R⁸)₂or R⁹ OC(O)NR⁸ --.

A fourth subset of compounds of the invention is represented by formulaId: ##STR5## wherein: each R² is independently selected from: hydrogenand C₁ -C₆ alkyl;

R³ and R⁴ are independently selected from H, F, Cl, Br, N(R⁸)₂, CF₃,NO₂, (R⁸)O--, (R⁹)S(O)_(m) --, (R⁸)C(O)NH--, H₂ N--C(NH)--, (R⁸)C(O)--,(R⁸)OC(O)--, N₃, CN, (R⁹)OC(O)NR⁸ --, C₁ -C₂₀ alkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heterocyclyl;

A³ represents --NR⁵ --S(O)_(m) -- or --S(O)_(m) --NR⁵ --;

R⁵ is selected from: hydrogen and C₁ -C₆ alkyl, unsubstituted orsubstituted witha group selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclyl, unsubstituted or substitutedC₃ -C₁₀ cycloalkyl, N(R⁸)₂, CF₃, NO₂, (R⁸)O--, (R⁹)S(O)_(m) --,(R⁸)C(O)NH--, H₂ N--C(NH)--, (R⁸)C(O)--, (R⁸)OC(O)--, N₃, CN(R⁹)OC(O)NR⁸ --; and R⁸, R⁹, m and p are as originally defined.

Specific examples of compounds of the invention are: ##STR6## and thepharmaceutically acceptable salts thereof.

The pharmaceutically acceptable salts of the compounds of this inventioninclude the conventional non-toxic salts of the compounds of thisinvention as formed, e.g., from non-toxic inorganic or organic acids.For example, such conventional non-toxic salts include those derivedfrom inorganic acids such as hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, nitric and the like: and the salts prepared fromorganic acids such as acetic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.

The pharmaceutically acceptable salts of the compounds of this inventioncan be synthesized from the compounds of this invention which contain abasic moiety by conventional chemical methods. Generally, the salts areprepared either by ion exchange chromatography or by reacting the freebase with stoichiometric amounts or with an excess of the desiredsalt-forming inorganic or organic acid in a suitable solvent or variouscombinations of solvents.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in Schemes 1-7, in addition to otherstandard manipulations such as ester hydrolysis, cleavage of protectinggroups, etc., as may be known in the literature or exemplified in theexperimental procedures. Substituents R' and R'CH₂ --, as shown in theSchemes, represent the substituents R⁸, R⁹ and others, depending on thecompound of the instant invention that is being synthesized. Thevariable p' represents p-1.

These reactions may be employed in a linear sequence to provide thecompounds of the invention or they may be used to synthesize fragmentswhich are subsequently joined by the alkylation reactions described inthe Schemes.

Synopsis of Schemes

The requisite intermediates are commercially available or can beprepared according to literature procedures. The Schemes illustrate thesynthesis of certain preferred embodiments of the instant invention,wherein the variable W is present as an imidazolyl moiety that issubstituted. Substituted protected imidazole alkanols II can be preparedby methods, such as those described by F. Schneider, Z. Physiol. Chem.,3:206-210 (1961) and C. P. Stewart, Biochem. Journal, 17:130-133(1923).Benzylation and deprotection of the imidazole alkanol provides anintermediate which can be oxidized to the corresponding aldehyde.

The aldehyde IV is reacted with a suitably substituted amine. Theintermediate can then be reacted with a sulfinyl chloride.

Syntheses of suitably substituted aldehydes are illustrated wherein thevariable W is present as a pyridyl moiety. Similar synthetic strategiesfor preparing alkanols that incorporate other heterocyclic moieties forvariable W are also well known in the art.

The sulfinamide can be formed by converting a hydroxyl group to asulfinyl chloride, and then reacting the sulfinyl chloride with theappropriately substituted amine. The resulting sulfinamide canthereafter be oxidized with, e.g., periodate, to produce sulfonamides inaccordance with formula I. Likewise, by reacting the precursor aminewith an alkylating agent, substitution on the sulfonamide nitrogen atomcan be realized. ##STR7##

The instant compounds are useful in the treatment of cancer. Cancerswhich may be treated with the compounds of this invention include, butare not limited to, colorectal carcinoma, exocrine pancreatic carcinoma,myeloid leukemias and neurological tumors. Such tumors may arise bymutations in the ras genes themselves, mutations in the proteins thatcan regulate Ras activity (i.e., neurofibromin (NF-1), neu, scr, abl,lck, fyn) or by other mechanisms.

The compounds of the instant invention inhibit farnesyl-proteintransferase and farnesylation of the oncogene protein Ras. The instantcompounds may also inhibit tumor angiogenesis, thereby affecting thegrowth of tumors (J. Rak et al. Cancer Research, 55:4575-4580 (1995)).Such anti-angiogenic properties of the instant compounds may also beuseful in the treatment of certain forms of blindness related to retinalvascularization.

The compounds of this invention are also useful for inhibiting otherdiseases where Ras proteins are aberrantly activated as a result ofoncogenic mutation in other genes (i.e., the Ras gene itself is notactivated by mutation to an oncogenic form) with said inhibition beingaccomplished by the administration of an effective amount of thecompounds of the invention to a mammal in need of such treatment. Forexample, a component of NF-1 is a benign proliferative disorder.

The instant compounds may also be useful in the treatment of viralinfections, in particular in the treatment of hepatitis delta andrelated viruses (J. S. Glenn et al. Science, 256:1331-1333 (1992).

The compounds of the instant invention are also useful in the preventionof restenosis after percutaneous transluminal coronary angioplasty byinhibiting neointimal formation (C. Indolfi et al. Nature medicine,1:541-545(1995).

The instant compounds may also be useful in the treatment and preventionof polycystic kidney disease (D. L. Schaffner et al. American Journal ofPathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al. FASEB Journal,2:A3160 (1988)).

The instant compounds may also be useful for the treatment of fungalinfections.

The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers or diluents, in the form of apharmaceutical composition, which is comprised of a compound of formulaI in combination with a pharmaceutically acceptable carrier. Thecompounds can be administered orally, topically, rectally, vaginallytransdermally or parenterally, including the intravenous, intramuscular,intraperitoneal and subcutaneous routes of administration.

For oral use, the compound is administered, for example, in the form oftablets or capsules, or as a solution or suspension. In the case oftablets for oral use, carriers which are commonly used include lactoseand corn starch; lubricating agents, such as magnesium stearate, arecommonly added. For oral administration in capsule form, diluents alsoinclude lactose and dried corn starch. When aqueous suspensions arerequired for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening and/orflavoring agents may be added. For intramuscular, intra-peritoneal,subcutaneous and intravenous use, sterile solutions of the activeingredient are usually prepared, the pH of the solution is suitablyadjusted and the product is buffered. For intravenous use, the totalconcentration is controlled to render the preparation substantiallyisotonic.

The compounds of the instant invention may also be co-administered withother well known therapeutic agents that are selected for theirparticular usefulness against the condition that is being treated. Forexample, the instant compounds may be useful in combination with knownanti-cancer and cytotoxic agents. Similarly, the instant compounds maybe useful in combination with agents that are effective in the treatmentand prevention of NF-1, restinosis, polycystic kidney disease,infections of hepatitis delta and related viruses and fungal infections.

If formulated as a fixed dose, such combination products employ acompound of this invention substantially within the dosage rangedescribed below and other pharmaceutically active agent(s) typicallywithin the acceptable dosage range. Compounds of the instant inventionmay alternatively be used sequentially with known pharmaceuticallyacceptable agent(s) when a combination formulation is inappropriate.

The daily dosage will normally be determined by the prescribingphysician, who may vary the dosage according to the age, weight, andresponse of the individual patient, as well as the severity of thepatient's condition.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount between about 0.1 mg/kg of body weight to about 60mg/kg of body weight per day, preferably of between 0.5 mg/kg of bodyweight to about 40 mg/kg of body weight per day.

The compounds of the instant invention are also useful as a component inan assay to rapidly determine the presence and quantity offarnesyl-protein transferase (FPTase) in a composition. Thus thecomposition to be tested may be divided and the two portions contactedwith mixtures which comprise a known substrate of FPTase (for example atetrapeptide having a cysteine at the amine terminus) and farnesylpyrophosphate and, in one of the mixtures, a compound of the instantinvention. After the assay mixtures are incubated for an sufficientperiod of time, well known in the art, to allow the FPTase tofarnesylate the substrate, the chemical content of the assay mixturesmay be determined by well known immunological, radiochemical orchromatographic techniques. Because the compounds of the instantinvention are selective inhibitors of FPTase, absence or quantitativereduction of the amount of substrate in the assay mixture without thecompound of the instant invention relative to the presence of theunchanged substrate in the assay containing the instant compound isindicative of the presence of FPTase in the composition to be tested.

It would be readily apparent to one of ordinary skill in the art thatsuch an assay as described above would be useful in identifying tissuesamples which contain farnesyl-protein transferase and quantitating theenzyme. Thus, potent inhibitor compounds of the instant invention may beused in an active site titration assay to determine the quantity ofenzyme in the sample. A series of samples composed of aliquots of atissue extract containing an unknown amount of farnesyl-proteintransferase, an excess amount of a known substrate of FPTase (forexample a tetrapeptide having a cysteine at the amine terminus) andfarnesyl pyrophosphate are incubated for an appropriate period of timein the presence of varying concentrations of a compound of the instantinvention. The concentration of a sufficiently potent inhibitor (i.e.,one that has a Ki substantially smaller than the concentration of enzymein the assay vessel) required to inhibit the enzymatic activity of thesample by 50% is approximately equal to half of the concentration of theenzyme in that particular sample.

EXAMPLE 1 N-1-(4-Cyanobenzyl)Imidazolyl-5-Methyl!-N-(Methyl)-3-ChlorobenzylsulfonamideHydrochloride

Step A: Preparation of 1-triphenylmethyl-4-(hydroxymethyl)imidazole

To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260mmol) in 250 mL of dry DMF at room temperature was added triethylamine(90.6 mL, 650 mmol). A white solid precipitated from the solution.Chlorotriphenylmethane (76.1 g, 273 mmol) in 500 mL of DMF was addeddropwise. The reaction mixture was stirred for 20 hours, poured overice, filtered, and washed with ice water. The resulting product wasslurried with cold dioxane, filtered, and dried in vacuo to provide thetitled product as a white solid which was sufficiently pure for use inthe next step.

Step B: Preparation of 1-triphenylmethyl-4-(acetoxymethyl)imidazole

Alcohol from Step A (260 mmol, prepared above) was suspended in 500 mLof pyridine. Acetic anhydride (74 mL, 780 mmol) was added dropwise, andthe reaction was stirred for 48 hours during which it becamehomogeneous. The solution was poured into 2 L of EtOAc, washed withwater (3×1 L), 5% aq. HCl soln. (2×1 L), sat. aq. NaHCO₃, and brine,then dried (Na₂ SO₄), filtered, and concentrated in vacuo to provide thecrude product. The acetate was isolated as a white powder (85.8 g, 86%yield for two steps) which was sufficiently pure for use in the nextreaction.

Step C: Preparation of 1-(4-cyanobenzyl)-5-(acetoxymethyl)imidazolehydrobromide

A solution of the product from Step B (85.8 g, 225 mmol) andα-bromo-ρ-tolunitrile (50.1 g, 232 mmol) in 500 mL of EtOAc was stirredat 60° C. for 20 hours, during which a pale yellow precipitate formed.The reaction was cooled to room temperature and filtered to provide thesolid imidazolium bromide salt. The filtrate was concentrated in vacuoto a volume 200 mL, reheated at 60° C. for two hours, cooled to roomtemperature, and filtered again. The filtrate was concentrated in vacuoto a volume 100 mL, reheated at 60° C. for another two hours, cooled toroom temperature, and concentrated in vacuo to provide a pale yellowsolid. All of the solid material was combined, dissolved in 500 mL ofmethanol, and warmed to 60 ° C. After two hours, the solution wasreconcentrated in vacuo to provide a white solid which was trituratedwith hexane to remove soluble materials. Removal of residual solvents invacuo provided the titled product hydrobromide as a white solid (50.4 g,67% yield, 89% purity by HPLC) which was used in the next step withoutfurther purification.

Step D: Preparation of 1-(4-cyanobenzyl)-5-(hydroxymethyl)imidazole

To a solution of the acetate from Step C (50.4 g, 150 mmol) in 1.5 L of3:1 THF/water at 0° C. was added lithium hydroxide monohydrate (18.9 g,450 mmol). After one hour, the reaction was concentrated in vacuo,diluted with EtOAc (3 L), and washed with water, sat. aq. NaHCO₃ andbrine. The solution was then dried (Na₂ SO₄), filtered, and concentratedin vacuo to provide the crude product (26.2 g, 82% yield) as a paleyellow fluffy solid which was sufficiently pure for use in the next stepwithout further purification.

Step E: Preparation of 1-(4-cyanobenzyl)-5-imidazolecarboxaldehyde

To a solution of the alcohol from Step D (21.5 g, 101 mmol) in 500 mL ofDMSO at room temperature was added triethylamine (56 mL, 402 mmol), thenSO₃ -pyridine complex (40.5 g, 254 mmol). After 45 minutes, the reactionwas poured into 2.5 L of EtOAc, washed with water (4×1 L) and brine,dried (Na₂ SO₄), filtered, and concentrated in vacuo to provide thealdehyde (18.7 g, 88% yield) as a white powder which was sufficientlypure for use in the next step without further purification.

Step F: Preparation of 1-(4-cyanobenzyl)-5-(methylamino)methyl!imidazole

To a suspension of methylamine hydrochloride in 5 mL dichloroethane at0° C. are added 4 Å sieves (0.5 g), followed by 1 mmol of the aldehydefrom Step E and 1.5 mmol Na(OAc)₃ BH. The reaction is stirred for 10minutes at 0° C., warmed to room temperature and stirred for 2 hours.The reaction is poured into EtOAc/ sat. NaHCO₃ solution. The organiclayer is washed with brine, dried (Na₂ SO₄), filtered, and concentratedin vacuo. The crude product is taken up in 10 mL dichloromethane and 2mL n-propylamine, stirred at room temperature for 1 hour, concentratedin vacuo , and purified by flash chromatography.

Step G: Preparation of 3-chlorobenzyl thioacetate

To a solution of 1 mmol 3-chlorobenzyl alcohol and 1 mmoltriphenylphosphine in 5 mL THF at 0° C., 1 mmol diethylazodicarboxylateis added. After stirring for 10 minutes, 1 mmol thioacetic acid isadded. The reaction is stirred for 3 hours, concentrated and purified byflash chromatography.

Step H: Preparation of 3-chlorobenzylsulfinyl chloride

To a -20° C. solution of the thioester from Step G (1 mmol) in 3 mL ofdichloromethane under argon are added 1 mmol acetic anhydride and 2 mmolsulfuryl chloride. The reaction is stirred for 1 hr during which timethe temperature is allowed to rise to -5° C. The mixture is concentratedin vacuo and the crude product used for coupling in the next step.

Step I: Preparation of N-1-(4-cyanobenzyl)imidazolyl-5-methyl!-N-(methyl)-3-chlorobenzylsulfinamide

To a 0° C. solution of the sulfinyl chloride from Step H (1 mmol) in 4mL dichloromethane is added a solution of 1 mmol triethylamine and 1mmol of the amine from Step F in 2 mL dichloromethane. The reaction isstirred overnight and the temperature is allowed to rise to roomtemperature. This mixture is poured into ethyl acetate, washed with sat.NaHCO₃ solution and brine, dried with Na₂ SO₄, concentrated and purifiedby flash chromatography.

Step J: Preparation of N-1-(4-cyanobenzyl)imidazolyl-5-methyl!-N-(methyl)-3-chlorobenzylsulfonamidehydrochloride

A solution of the sulfinamide from Step I (1 mmol) in 2 mL acetonitrileis cooled to 0° C. NaIO₄ is added (1.5 mmol) followed by a catalyticamount of RuCl₃.3H₂ O and 2 mL H₂ O. The reaction is stirred at roomtemperature for 1 hour, diluted with EtOAc, and washed with sat. NaHCO₃solution and brine, dried (Na₂ SO₄), filtered and concentrated. Theresulting product is purified by flash chromatography, then taken up indichloromethane, and treated with with excess ethereal HCl.Concentration in vacuo provides the titled product.

EXAMPLE 2 N-(3-Chlorobenzyl)-1-(4-Cyanobenzyl)-5-Imidazolyl!Methylsulfonamide Hydrochloride

Step A: Preparation of 1-(4-chlorobenzyl)-5-imidazolylmethyl sulfinylchloride

The titled compound is prepared from the alcohol from Step D of Example1 by the methods described in Steps G and H of Example 1.

Step B: Preparation of N-(3-chlorobenzyl)-1-(4-cyanobenzyl)-5-imidazolyl!methylsulfinamide

The sulinyl chloride from Step A is coupled with 3-chlorobenzylamineusing the method described in Step I of Example 1.

Step C: Preparation of N-(3-chlorobenzyl)-1-(4-cyanobenzyl)-5-imidazolyl!methylsulfonamide hydrochloride

The sulfinamide from Step B is oxidized to the sulfonamide and convertedto the HCl salt using the method described in Step J of Example 1.

EXAMPLE 3 N-3-(4-Cyanobenzyl)Pyridyl-4-Methyl!-N-(Methyl)-3-ChlorobenzylsulfonamideHydrochloride

Step A: Preparation of 3-(4-cyanobenzyl)pyridin-4-carboxylic acid methylester

A solution of 4-cyanobenzyl bromide (625 mg, 3.27 mmol) in dry THF (4mL)was added slowly over ˜3 min. to a suspension of activated Zn (dust; 250mg) in dry THF (2 mL) at 0° under an argon atmosphere. The ice-bath wasremoved and the slurry was stirred at room temperature for a further 30min. Then 3-bromopyridin-4-carboxylic acid methyl ester (540 mg. 2.5mmol) followed by dichlorobis(triphenylphosphine)nickel (II) (50 mg).The resultant reddish-brown mixture was stirred for 3 h at ˜40°-45° C.The mixture was cooled and distributed between EtOAc (100 ml) and 5%aqueous citric acid (50 mL). The organic layer was washed with H₂ O(2×50 mL), dried with Na₂ SO₄. After evaporation of the solvent theresidue was purified on silica gel, eluting with 35% EtOAc in hexane togive 420 mg as a clear gum. FAB ms (M+1) 253.

Step B: Preparation of 3-(4-cyanobenzyl)-4-(hydroxymethyl)pyridine

The title compound was obtained by sodium borohydride (300 mg) reductionof the ester from Step A (415 mg) in methanol (5 mL) at roomtemperature. After stirring for 4 h the solution was evaporated and theproduct was purified on silica gel, eluting with 2% methanol inchloroform to give the title compound. FAB ms (M+1) 225.

Step C: Preparation of 3-(4-cyanobenzyl)-4-pyridinal

The title compound was obtained by activated manganese dioxide (1.0 g)oxidation of the alcohol from Step B (240 mg, 1.07 mmol) in dioxane (10mL) at reflux for 30 min. Filtration and evaporation of the solventprovided title compound, mp 80°-83° C.

Step D: Preparation of 3-(4-cyanobenzyl)-4- (methylamino)methyl!pyridine

The titled compound is prepared from the pyridinal from Step C andmethylamine hydrochloride using the procedure in Step F of Example 1.

Step E: Preparation of N-3-(4-cyanobenzyl)pyridyl-4-methyl!-N-(methyl)-3-chlorobenzylsulfonamidehydrochloride

The titled compound is prepared from the amine from Step D and thesulfinyl chloride from Step H of Example 1 using the proceduresdescribed in Steps I and J of Example 1.

In vitro inhibition of ras farnesyl transferase

Assays of farnesyl-protein transferase. Partially purified bovine FPTaseand Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared asdescribed by Schaber et al., J. Biol. Chem. 265:14701-14704 (1990),Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNASU.S.A. 86:6630-6634 (1989), respectively. Bovine FPTase was assayed in avolume of 100 μl containing 100 mM N-(2-hydroxy ethyl)piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl₂, 5 mMdithiothreitol (DTT), 100 mM ³ H!-farnesyl diphosphate ( ³ H!-FPP; 740CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 μg/ml FPTase at31° C. for 60 min. Reactions were initiated with FPTase and stopped with1 ml of 1.0M HCL in ethanol. Precipitates were collected ontofilter-mats using a TomTec Mach II cell harvester, washed with 100%ethanol, dried and counted in an LKB β-plate counter. The assay waslinear with respect to both substrates, FPTase levels and time; lessthan 10% of the ³ H!-FPP was utilized during the reaction period.Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) andwere diluted 20-fold into the assay. Percentage inhibition is measuredby the amount of incorporation of radioactivity in the presence of thetest compound when compared to the amount of incorporation in theabsence of the test compound.

Human FPTase was prepared as described by Omer et al., Biochemistry32:5167-5176 (1993). Human FPTase activity was assayed as describedabove with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10μM ZnCl₂ and 100 nM Ras-CVIM were added to the reaction mixture.Reactions were performed for 30 min., stopped with 100 μl of 30% (v/v)trichloroacetic acid (TCA) in ethanol and processed as described abovefor the bovine enzyme.

In vivo ras farnesylation assay

The cell line used in this assay is a v-ras line derived from eitherRat1 or NIH3T3 cells, which expressed viral Ha-ras p21. The assay isperformed essentially as described in DeClue, J. E. et al., CancerResearch 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluencyare treated with the test compound (final concentration of solvent,methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37° C., thecells are labelled in 3 ml methionine-free DMEM supplemeted with 10%regular DMEM, 2% fetal bovine serum and 400 mCi ³⁵ S!methionine (1000Ci/mmol). After an additional 20 hours, the cells are lysed in 1 mllysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl₂ /1 mM DTT/10 mg/mlaprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and thelysates cleared by centrifugation at 100,000×g for 45 min. Aliquots oflysates containing equal numbers of acid-precipitable counts are boughtto 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitatedwith the ras-specific monoclonal antibody Y13-259 (Furth, M. E. et al.,J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at4° C., 200 ml of a 25% suspension of protein A-Sepharose coated withrabbit anti rat IgG is added for 45 min. The immunoprecipitates arewashed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1%Triton X-100.0.5% deoxycholate/0.1%/SDS/0.1M NaCl) boiled in SDS-PAGEsample buffer and loaded on 13% acrylamide gels. When the dye frontreached the bottom, the gel is fixed, soaked in Enlightening, dried andautoradiographed. The intensities of the bands corresponding tofarnesylated and nonfarnesylated ras proteins are compared to determinethe percent inhibition of farnesyl transfer to protein.

In vivo growth inhibition assay

To determine the biological consequences of FPTase inhibition, theeffect of the compounds of the instant invention on theanchorage-independent growth of Rat1 cells transformed with either av-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Rafand v-Mos maybe included in the analysis to evaluate the specificity ofinstant compounds for Ras-induced cell transformation.

Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded ata density of 1×10⁴ cells per plate (35 mm in diameter) in a 0.3% topagarose layer in medium A (Dulbecco's modified Eagle's mediumsupplemented with 10% fetal bovine serum) over a bottom agarose layer(0.6%). Both layers contain 0.1% methanol or an appropriateconcentration of the instant compound (dissolved in methanol at 1000times the final concentration used in the assay). The cells are fedtwice weekly with 0.5 ml of medium A containing 0.1% methanol or theconcentration of the instant compound. Photomicrographs are taken 16days after the cultures are seeded and comparisons are made.

What is claimed is:
 1. A compound represented by formula I: ##STR8## or a pharmaceutically acceptable salt thereof, wherein: R^(1a), R^(1b) and R² are independently selected from the group consisting of: hydrogen, aryl, heterocyclyl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R⁸ O--, R⁹ S(O)_(m) --, (R⁸)₂ NC(O)--, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ NC(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, N₃, --N(R⁸)₂, R⁹ OC(O)NR⁸ -- and C₁ -C₆ alkyl, unsubstituted or substituted by 1-3 groups selected from the group consisting of: halo, aryl, heterocyclyl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R⁸ O--, R⁹ S(O)_(m) --, R⁸ C(O)NR⁸ --, CN, (R⁸)₂ NC(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, N₃, --N(R⁸)₂ and R⁹ OC(O)NR⁸ --;R³ and R⁴ are independently selected from the group consisting of: H, F, Cl, Br, --NR⁸ ₂, CF₃, NO₂, R⁸ O--, R⁹ S(O)_(m) --, (R⁸)₂ NC(O)--, R⁸ C(O)NH--, H₂ NC(NH)--, R⁸ C(O)--, R⁸ OC(O)--, N₃, CN, R⁹ OC(O)NR⁸ --, C₁ -C₂₀ alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl; A³ is selected from: --NR⁵ S(O)_(m) -- or --S(O)_(m) NR⁵ --, with m equal to 0, 1 or 2, and R⁵ selected from the group consisting of: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C₃ -C₁₀ cycloalkyl, and C₁ -C₆ alkyl, unsubstituted or substituted with 1-3 members selected from the group consisting of: unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C₃ -C₁₀ cycloalkyl, --N(R⁸)₂, --CF₃, --NO₂, (R⁸)O--, (R⁹)S(O)_(m) --, (R⁸)C(O)NH--, H₂ NC(NH)--, (R⁸)C(O)--, (R⁸)OC(O)--, N₃, CN and (R⁹)OC(O)NR⁸ --; R⁶ and R⁷ are independently selected from the group consisting of: hydrogen, aryl, heterocyclyl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁₋₆ perfluoroalkyl, F, Cl, Br, R⁸ O--, R⁹ S(O)_(m) --, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ NC(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, N₃, --N(R⁸)₂, R⁹ OC(O)NR⁸ -- and C₁ -C₆ alkyl unsubstituted or substituted by 1-3 groups selected from: aryl, heterocyclyl, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R⁸ O--, R⁹ S(O)_(m) --, R⁸ C(O)NR⁸ --, CN, (R⁸)₂ NC(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, N₃, --N(R⁸)₂ and R⁹ OC(O)NR⁸ --; each R⁸ is independently selected from hydrogen, C₁ -C₆ alkyl, aryl and aralkyl; each R⁹ is independently selected from C₁ -C₆ alkyl and aryl; A¹ and A² are independently selected from the group consisting of: a bond, --CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR⁸ --, --NR⁸ C(O)--, --O--, --N(R⁸)--, --S(O)₂ N(R⁸)--, --N(R⁸)S(O)₂ --, and S(O)_(m) ; X represents aryl or heteroaryl; V is selected from the group consisting of: hydrogen, heterocyclyl, aryl, C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C₂ -C₂₀ alkenyl, provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; W represents heterocyclyl; each n and p independently represents 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen, and t is
 1. 2. A compound in accordance with claim 1 wherein R^(1a), R^(1b) and R² are independently selected from the group consisting of: hydrogen, --N(R⁸)₂, R⁸ C(O)NR⁸ -- and C1-6 alkyl, unsubstituted or substituted with 1-2 groups selected from unsubstituted or substituted aryl, --N(R⁸)₂, R⁸ O-- and R⁸ C(O)NR⁸ --.
 3. A compound in accordance with claim 1 wherein R³ and R⁴ are selected from: hydrogen and C₁ -C₆ alkyl.
 4. A compound in accordance with claim 1 wherein A³ represents NR⁵ S(O)_(m), in which m represents 2 and R⁵ represents hydrogen.
 5. A compound in accordance with claim 1 wherein R⁶ represents hydrogen, unsubstituted or substituted C₁ -C₆ alkyl.
 6. A compound in accordance with claim 1 wherein R⁷ represents H or unsubstituted C₁₋₆ alkyl.
 7. A compound in accordance with claim 1 wherein R⁸ represents H or C₁₋₆ alkyl, and R⁹ is C₁₋₆ alkyl.
 8. A compound in accordance with claim 1 wherein A¹ and A² are independently selected from: a bond, --C(O)NR⁸ --, --NR⁸ C(O)--, --O--, --N(R⁸)--, --S(O)₂ N(R⁸)-- and --N(R⁸)S(O)₂ --.
 9. A compound in accordance with claim 1 wherein V is selected from hydrogen, heterocyclyl and aryl.
 10. A compound in accordance with claim 1 wherein V represents phenyl.
 11. A compound in accordance with claim 1 wherein X represents aryl.
 12. A compound in accordance with claim 11 wherein X represents phenyl.
 13. A compound in accordance with claim 1 wherein W is heterocyclyl selected from the group consisting of: imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl.
 14. A compound in accordance with claim 10 wherein W is selected from imidazolyl and pyridyl.
 15. A compound in accordance with claim 1 wherein m is 0 or
 2. 16. A compound in accordance with claim 1 wherein n and p are 0, 1, 2 or
 3. 17. A compound in accordance with claim 1 represented by formula Ia: ##STR9## wherein: R³, R⁴, A³, R⁸, R⁹, m, n, p and r are as originally defined;each R^(1a) and R² is independently selected from hydrogen and C₁ -C₆ alkyl; each R^(1b) is independently selected from: hydrogen, aryl, heterocyclyl, C₃₋₁₀ cycloalkyl, C₂₋₆ alkenyl, R⁸ O--, --N(R⁸)₂ and C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocyclyl, cycloalkyl, alkenyl, R⁸ O-- and --N(R⁸)₂ ; R⁵ is selected from the group consisting of: hydrogen and C₁ -C₆ alkyl, unsubstituted or substituted with 1-3 members selected from the group consisting of: unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C₃ -C₁₀ cycloalkyl, --N(R⁸)₂, --CF₃, --NO₂, (R⁸)O--, (R⁹)S(O)_(m) --, (R⁸)C(O)NH--, H₂ NC(NH)--, (R⁸)C(O)--, (R⁸)OC(O)--, N₃, CN and (R⁹)OC(O)NR⁸ --; R⁶ is independently selected from: hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R⁸ O--, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ --, and C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R⁸ O--, R⁸ C(O)NR⁸ --, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, --N(R⁸)₂ and R⁹ OC(O)NR⁸ --; R⁷ is H or unsubstituted C₁₋₆ alkyl; A¹ and A² are independently selected from: a bond, --CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR⁸ --, O, --N(R⁸)-- and S(O)_(m) ; and V is selected from: hydrogen; aryl; heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl and thienyl; C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and C₂ -C₂₀ alkenyl, provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogen if A¹ is a bond and A² is S(O)_(m).
 18. A compound in accordance with claim 1 represented by formula Ib: ##STR10## wherein: R^(1a), R^(1b), R², A¹, A², R³, R⁴, R⁵, R⁶, R⁸, R⁹, m, n, p and r are as originally defined;R⁷ is selected from: hydrogen and unsubstituted C₁ -C₆ alkyl; V is selected from: hydrogen, heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, aryl, C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C₂ -C₂₀ alkenyl, provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; and W represents heterocyclyl selected from pyrrolidinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl and isoquinolinyl.
 19. A compound in accordance with claim 1 represented by formula Ic: ##STR11## wherein: each R² is independently selected from hydrogen and C₁ -C₆ alkyl;R³, R⁴, A³, R⁸, R⁹, m and p are as originally defined; each R⁵ is selected from: hydrogen and C₁ -C₆ alkyl unsubstituted or substituted with 1-3 groups selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C₃ -C₁₀ cycloalkyl, --N(R⁸)₂, --CF₃, --NO₂, (R⁸)O--, (R⁹)S(O)_(m) --, (R⁸)C(O)NH--, H₂ NC(NH)--, (R⁸)C(O)--, (R⁸)OC(O)--, N₃, --CN and (R⁹)OC(O)NR⁸ --; and R⁶ is selected from the group consisting of: hydrogen, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R⁸ O--, R⁸ C(O)NR⁸ --, CN, NO₂, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O)--, R⁸ OC(O)--, --N(R⁸)₂, or R⁹ OC(O)NR⁸ -- and C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R⁸ O--, R⁸ C(O)NR⁸ --, (R⁸)₂ N--C(NR⁸)--, R⁸ C(O), R⁸ OC(O)--, --N(R⁸)₂ or R⁹ OC(O)NR⁸ --.
 20. A compound in accordance with claim 1 represented by formula Id: ##STR12## wherein: each R² is independently selected from: hydrogen and C₁ -C₆ alkyl;R³ and R⁴ are independently selected from H, F, Cl, Br, N(R⁸)₂, CF₃, NO₂, (R⁸)O--, (R⁹)S(O)_(m) --, (R⁸)C(O)NH--, H₂ N--C(NH)--, (R⁸)C(O)--, (R⁸)OC(O)--, N₃, CN, (R⁹)OC(O)NR⁸ --, C₁ -C₂₀ alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl; A³ represents --NR⁵ --S(O)_(m) -- or --S(O)_(m) --NR⁵ --; R⁵ is selected from: hydrogen and C₁ -C₆ alkyl, unsubstituted or substituted witha group selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C₃ -C₁₀ cycloalkyl, N(R⁸)₂, CF₃, NO₂, (R⁸)O--, (R⁹)S(O)_(m) --, (R⁸)C(O)NH--, H₂ N--C(NH)--, (R⁸)C(O)--, (R⁸)OC(O)--, N₃, CN (R⁹)OC(O)NR⁸ --.
 21. A pharmaceutical composition which comprises a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
 22. A method of inhibiting farnesyl-protein transferase in a mammalian patient in need of such treatment which comprises administering to said mammal a compound in accordance with claim
 1. 23. A method of treating cancer in a mammalian patient in need of such treatment which comprises administering to said patient an anti-cancer effective amount of a compound in accordance with claim
 1. 24. A method of treating cancer in accordance with claim 21, wherein the cancer treated is selected from colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemia and neurological tumors.
 25. A method of treating neurofibromin benign proliferative disorder in a mammalian patient in need of such treatment which comprises administering to said patient an effective amount of a compound of claim
 1. 26. A method of treating blindness related to retinal vascularization in a mammalian patient in need of such treatment which comprises administering to said patient an amount of a compound of claim 1 which is effective for treating blindness related to retinal vascularization.
 27. A method of treating hepatitis delta or a related viral infection in a mammalian patient in need of such treatment which comprises administering to said patient an anti-viral effective amount of a compound of claim
 1. 28. A method of preventing restenosis in a mammalian patient in need of such treatment which comprises administering to said patient an amount of a compound of claim 1 which is effective for preventing restenosis.
 29. A method of treating polycystic kidney disease in a mammalian patient in need of such treatment which comprises administering to said patient an amount of a compound of claim 1 which is effective for treating polycystic kidney disease.
 30. A method of treating or preventing a disease selected from cancer, neurofibromin benign proliferative disorder, blindness related to retinal vascularization, infections from hepatitis delta and related viruses, restenosis and polycystic kidney disease, in a mammalian patient in need of such treatment which comprises administering to said patient an effective amount of a a compound of claim
 1. 31. A compound in accordance with claim 1 represented by the formula: ##STR13## or a pharmaceutically acceptable salt thereof. 